JPH03505740A - Method for producing 3-desoxy-4-ene steroid - Google Patents
Method for producing 3-desoxy-4-ene steroidInfo
- Publication number
- JPH03505740A JPH03505740A JP2504118A JP50411890A JPH03505740A JP H03505740 A JPH03505740 A JP H03505740A JP 2504118 A JP2504118 A JP 2504118A JP 50411890 A JP50411890 A JP 50411890A JP H03505740 A JPH03505740 A JP H03505740A
- Authority
- JP
- Japan
- Prior art keywords
- group
- methylene
- hydrogen atom
- represent
- ene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- 150000003431 steroids Chemical class 0.000 title abstract description 10
- -1 fluoromethylene group Chemical group 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 11
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims abstract description 9
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 16
- 239000012279 sodium borohydride Substances 0.000 claims description 16
- 239000011541 reaction mixture Substances 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 5
- 150000001735 carboxylic acids Chemical class 0.000 claims description 5
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- PTPHNYFLJRHMHK-DYKIIFRCSA-N (8r,9s,10r,13s,14s,17s)-10,13-dimethyl-2,3,6,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-ol Chemical compound C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 PTPHNYFLJRHMHK-DYKIIFRCSA-N 0.000 description 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- YNVGQYHLRCDXFQ-XGXHKTLJSA-N Lynestrenol Chemical compound C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 YNVGQYHLRCDXFQ-XGXHKTLJSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910052776 Thorium Inorganic materials 0.000 description 1
- AVAYCNNAMOJZHO-UHFFFAOYSA-N [Na+].[Na+].[O-]B[O-] Chemical compound [Na+].[Na+].[O-]B[O-] AVAYCNNAMOJZHO-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940090961 chromium dioxide Drugs 0.000 description 1
- IAQWMWUKBQPOIY-UHFFFAOYSA-N chromium(4+);oxygen(2-) Chemical compound [O-2].[O-2].[Cr+4] IAQWMWUKBQPOIY-UHFFFAOYSA-N 0.000 description 1
- AYTAKQFHWFYBMA-UHFFFAOYSA-N chromium(IV) oxide Inorganic materials O=[Cr]=O AYTAKQFHWFYBMA-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001910 lynestrenol Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 ３−デシキシ−４−エン−ステロイドの製造方法本発明は、一般式Ｉ： Ｒ１、Ｒ２およびＲ３は水素原子またはメチル基を表わし、 Ｒ４は低級アルキル基、フェニル基または、遊離したまたはエステル化したまた はエーテル化したヒドロキシ基を表わし、 Ｒ５は水素原子、ビニル基または基−ｃ＝ｃＲ６を表わしくその際Ｒ６は水素原 子、最高で４個の炭素原子を有するアルキル基またはハロゲン原子を表わす）、 Ｘはメチレン基、フルオロメチレン基、エチリデン基またはビニリデン基を表わ し、 ＹおよびＵはメチレン基またはエチリデン基を表わしＺはメチレン基、エチリデ ン基、ビニリデン基、クロロメチレン基またはヒドロキシメチレン基を表わし、 および 二＝で表わされる結合は３個の単結合または１個の二重結合および２個の単結合 または共役二重結合を表わす］で示される３−デシキシ−４−エン−ステロイド の製造方法において、一般式■： ［式中、ニニニ＝シ、Ｒ１、Ｒ２、Ｒ３、ｘ１Ｙ％ＺおよびＵは前記したものを 表わし、２２番およびＲ’５はＲ４およびＲ５と同様かまたはオキソ基を表わす ］で示される３−オキソ−４−エン−ステロイドを、トリフルオロ酢酸またはト リクロロ酢酸、場合によりさらにもう１つのカルボン酸および水素化ホウ素ナト リウムからの反応混合物で還元することを特徴とする３−デシキシ−４−エン− ステロイドの製造方法に関する一般式Ｉの３−デシキシ−４−エン−ステロイド は薬学的に有効な公知の物質または薬学的に有効の化合物を製造するための価値 ある中間生成物である（西ドイツ国特許第２３６１１２０号、欧州特許第１７０ ９６号および同第３４１１４号明細書）。[Detailed description of the invention] Process for producing 3-decoxy-4-ene steroid R1, R2 and R3 represent a hydrogen atom or a methyl group, R4 is a lower alkyl group, a phenyl group, or a free or esterified group. represents an etherified hydroxy group, R5 represents a hydrogen atom, a vinyl group, or a group -c=cR6, in which case R6 is a hydrogen atom. represents an alkyl group having up to 4 carbon atoms or a halogen atom), X represents a methylene group, a fluoromethylene group, an ethylidene group or a vinylidene group death, Y and U represent a methylene group or an ethylidene group, and Z represents a methylene group or an ethylidene group. represents a vinylidene group, a vinylidene group, a chloromethylene group or a hydroxymethylene group, and The bond represented by 2= is 3 single bonds or 1 double bond and 2 single bonds. or a conjugated double bond] 3-decoxy-4-ene-steroid In the manufacturing method, the general formula ■: [In the formula, Ninini=shi, R1, R2, R3, x1Y%Z and U are as described above 22 and R'5 are the same as R4 and R5 or represent an oxo group. ] The 3-oxo-4-ene steroid represented by Lichloroacetic acid, optionally another carboxylic acid and sodium borohydride 3-decoxy-4-ene- characterized in that it is reduced with a reaction mixture from 3-decoxy-4-ene-steroids of general formula I regarding the process for producing steroids is a known pharmaceutically active substance or value for producing a pharmaceutically active compound. It is a certain intermediate product (West German Patent No. 2361120, European Patent No. 170). No. 96 and Specification No. 34114).
たとえば、一般式■ａ： Ｒ′３は水素原子またはメチル基を表わし、Ｒ“４はヒドロキシ基または４個ま での炭素原子を有するアルカノイルオキシ基を表わし、 Ｒ’５は水素原子、ビニル基、エチニル基、クロロエチニル基またはｌ−プロピ ニル基を表わし、Ｘはメチレン基またはビニリデン基を表わし、二重は１つの単 結合または１つの二重結合を表わす］で示される３−デシキシ−４−エン−ステ ロイドは著しいゲスターゲン作用により優れている。この種のゲスターゲン作用 ステロイドの例は、リネストレノール（１７α−エチニル−４−ニストレン−１ ７β−オール）およびデシゲストレル（１７σ−エチニル−１８−メチル−１１ −メチレン−４−ニストレン−１７β−オール）である。For example, general formula ■a: R'3 represents a hydrogen atom or a methyl group, and R'4 represents a hydroxy group or 4 or more represents an alkanoyloxy group having a carbon atom, R'5 is a hydrogen atom, a vinyl group, an ethynyl group, a chloroethynyl group, or a l-propylene group. represents a nyl group, X represents a methylene group or a vinylidene group, and a double represents one single bond or one double bond] Lloyd is superior due to its pronounced gestagen action. This type of gestagen action Examples of steroids are linestrenol (17α-ethynyl-4-nystren-1 7β-ol) and decigestrel (17σ-ethynyl-18-methyl-11 -methylene-4-nystrene-17β-ol).
公知の先行技術により、一般式Ｉの３−デシキシ−４−エン−ステロイドは、３ −オキシ−４−エン−ステロイドから、たとえばエタンジチオールを用いてチオ ケタールに変え、液体アンモニア中でナトリウムまたはリチウムを用いてチオケ タール基を分割することにより製造される。この方法は高いエネルギーコストを 費すために著しく費用がかかり、さらに著しい臭いのために著しく環境を害する という欠点がある。According to the known prior art, 3-decoxy-4-ene-steroids of general formula I are -oxy-4-ene-steroids, for example using ethanedithiol. ketal and thioke with sodium or lithium in liquid ammonia. Produced by splitting the tar group. This method has high energy costs It is extremely expensive to use and is also extremely harmful to the environment due to its pronounced odor. There is a drawback.
これに対して本発明による方法は、容易に実施でき、あまり環境を害することが ないｌ工程反応であり、その際公知の２工程方法の場合と同様に理論値の約６０ 〜８５％の収率が達成される。In contrast, the method according to the invention is easy to implement and causes less environmental damage. 60% of the theoretical value, as in the known two-step process. Yields of ~85% are achieved.
本発明による方法は、最初に水素化ホウ素ナトリウムを−１０”Ｃ〜＋２０℃の 温度でトリフルオロ酢酸またはトリクロロ酢酸、場合によりその他のカルボン酸 中で反応させるように実施される。この場合水素の発生の結果、著しく発泡する Ｉ；め、反応を開始する前にトリハロゲン酢酸、有利になおアセトニトリルを添 加し、それにより発泡は十分に抑えられる。トリフルオロ酢酸を使用する場合に これは必要であるが、トリクロロ酢酸を使用する場合には、トリハロゲン酢酸に さらに他のカルボン酸を添加することは必要ではない。The method according to the invention involves first adding sodium borohydride to a temperature between -10"C and +20C. trifluoroacetic acid or trichloroacetic acid and optionally other carboxylic acids at temperature The reaction is carried out inside the reactor. In this case, significant foaming occurs as a result of the evolution of hydrogen. I; before starting the reaction, trihalogenated acetic acid, preferably also acetonitrile, is added. In this way, foaming can be sufficiently suppressed. When using trifluoroacetic acid This is necessary, but if trichloroacetic acid is used, It is not necessary to add further other carboxylic acids.
このようなカルボン酸はモノカルボン酸、ジカルボン酸、酪酸、ピバリン酸、コ ハク酸、クエン酸または特に著しく廉価な酢酸である。後述する実施例において 、水酸化ナトリウムとトリハロゲン酢酸と反応させるために、常に反応剤／溶剤 混合物の過剰量を使用し、その結果透明な溶液が形成される。工業的に実施する ためにそれぞれ必要な最低量の反応剤／溶剤混合物および最適なその組成は、個 々の場合で当業者が周知の予備実験により測定しなければならない。Such carboxylic acids include monocarboxylic acids, dicarboxylic acids, butyric acid, pivalic acid, and co-carboxylic acids. Huccinic acid, citric acid or especially the extremely inexpensive acetic acid. In the examples described later , always reactant/solvent to react with sodium hydroxide and trihalogenacetic acid Use an excess of the mixture so that a clear solution is formed. carry out industrially The minimum amount of reactant/solvent mixture required and its optimum composition for each It must be determined in each case by preliminary experiments well known to those skilled in the art.
こうして製造した水素化ホウ素ナトリウム／トリハロゲン酢酸反応混合物（場合 によりさらに他のカルボン酸を含有する）中に、不活性溶剤中に溶かしｔ；反応 すべきステロイドを投入することができる。しかし、この反応混合物をステロイ ド溶液中に投入するほうがしばしばより純粋な生成物を得る。反応温度は約−３ ０℃〜＋３０℃である。一方の成分を他方に添加する最適速度は、当業者に周知 の予備実験で測定しなければならない。長すぎる添加速度は反応の進行それ自体 にとって、たいていは有利でない。反応時間は原則として５分〜１２０分までで ある。The sodium borohydride/trihalogenacetic acid reaction mixture thus prepared (if further containing other carboxylic acids), dissolved in an inert solvent; You can put in steroids if you should. However, this reaction mixture A purer product is often obtained by charging the product into a liquid solution. The reaction temperature is about -3 It is 0°C to +30°C. The optimal rate of addition of one component to the other is well known to those skilled in the art. must be measured in preliminary experiments. Addition rate that is too long will prevent the reaction from proceeding. It is usually not advantageous for As a general rule, the reaction time is 5 minutes to 120 minutes. be.
反応すべきステロイドをどの不活性溶剤に溶かすかはあまり重要ではない。適当 な不活性溶剤はたとえばエーテル、たとえばジエチルエーテル、ジイソプロピル エーテル、ジオキサン、テトラヒドロフランまたは１．２−ジメトキシエタン、 塩素化炭化水素、！；とえばメチレンクロリド、クロロホルム、四塩化炭素また は液体芳香族炭化水素、ベンゼン、トルエンまたはキシレンである。It is not very important in which inert solvent the steroid to be reacted is dissolved. suitable Examples of suitable inert solvents include ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or 1,2-dimethoxyethane, Chlorinated hydrocarbons! e.g. methylene chloride, chloroform, carbon tetrachloride or is a liquid aromatic hydrocarbon, benzene, toluene or xylene.
すでに前記したように、一般式■の反応すべき３−オキソ−４−エン−ステロイ ドは、単独のまたは共役の二重結合を１５位、１４位および／または１６位に有 し、その際置換基Ｒ５のビニル基またはビニリデン基Ｘ８よび／またはＺを有す るおよび／または置換基Ｒ５中に三重結合を有し、これらの原子団は反応の際に 攻撃されない。エーテル化しｔ：ヒドロキシ基Ｒ４（有利に１〜４個の炭素原子 を有するアルキルエーテル、ｔ；とえばメチルエーテル、エチルエーテルまたは ｔ−ブチルエーテル）を有する３−オキソ−４−エン−ステロイドは分割されな いが、エステル化したヒドロキシ基Ｒ４（有利に１〜６個の炭素原子を有するア ルカノイルエステル、たとえばアセテート、プロピオネート、ビバレートまｔ二 はベンゾイルエステルる３−オキソ−４−エン−ステロイドの場合、部分的にエ ステル交換するまたは還元して分割することができる。ハロゲン原子（有利にフ ッ素原子まＩ；は塩素原子を有する３−オキソ−４−エン−ステロイドの場合、 反応の間にハロゲン分割は行なわれない。１７位にオキソ基を有する３−オキソ −４−エン−ステロイドを還元して相応する１７β−ヒドロキシ−ステロイドに し、これは次の実施例に記載したように問題なく再度１７−オキソ−ステロイド に酸化することができる次に本発明を実施例により詳説する。As already mentioned above, the 3-oxo-4-ene-steroid of general formula (2) to be reacted with has a single or conjugated double bond at position 15, 14 and/or 16. , in which the substituent R5 has a vinyl group or a vinylidene group X8 and/or Z and/or has a triple bond in the substituent R5, and these atomic groups are Not attacked. etherified t: hydroxy group R4 (preferably 1 to 4 carbon atoms) an alkyl ether having t; for example methyl ether, ethyl ether or 3-oxo-4-ene-steroids with t-butyl ether) are not resolved. However, the esterified hydroxy group R4 (advantageously having 1 to 6 carbon atoms) Lucanoyl esters, such as acetate, propionate, vivalate, etc. In the case of 3-oxo-4-ene steroids, which are benzoyl esters, It can be transformed or reduced and divided. A halogen atom (preferably a halogen atom) In the case of a 3-oxo-4-ene steroid having a chlorine atom, No halogen splitting takes place during the reaction. 3-oxo with oxo group at position 17 -4-ene-steroids are reduced to the corresponding 17β-hydroxy-steroids , which was successfully reconstituted with 17-oxo-steroids as described in the following example. Next, the present invention will be explained in detail with reference to Examples.
例 ｌ トリフルオロ酢酸２ ｍＱ，酢酸２ｍＱおよびアセトニトリル２ｍＱに、氷／水 で冷却しなから水不含の水素化ホウ素ナトリウム２２０ｍｇを少しずつ添加した 。引き続き乾燥メチレンクロリド５’ｍ（＋中の１７β−ヒドロキシ−４−アン ドロステン−３−オン ２８８ｍｇを滴加し、室温で撹拌し、３０分後に飽和炭 酸水素ナトリウム溶液を注意深く添加した。メチレンクロリドで抽出し、水で中 性に洗浄し、硫酸マグネシウムで乾燥した。残分をメチレンクロリド／メタノー ル（９９＋１）を用いるシリカゲルカラムのクロマトグラフィーにかけると、融 点ｌ゛４６〜１４９℃の４−アンドロステン−１７β−オール ２４０ｍｇが得 られｌ；。Example l Add 2 mQ of trifluoroacetic acid, 2 mQ of acetic acid, and 2 mQ of acetonitrile to ice/water. After cooling, 220 mg of water-free sodium borohydride was added little by little. . Then add 5'm of dry methylene chloride (17β-hydroxy-4-an Drosten-3-one (288 mg) was added dropwise, stirred at room temperature, and after 30 minutes, saturated charcoal was added. The sodium oxyhydrogen solution was added carefully. Extract with methylene chloride and medium with water. and dried over magnesium sulfate. The residue is converted into methylene chloride/methanol. Chromatography on a silica gel column using a column (99+1) reveals that the melt Obtained 240 mg of 4-androsten-17β-ol at a temperature of 46 to 149°C. It's late.
例 ２ トリクロロ酢酸５ｍｉ２およびアセトニトリル５ｍ４に、氷／水で冷却しながら 、水不含の水素化ホウ素ナトリウム ３７０ｍｇを少しずつ添加した。引き続き 、メチレンクロリ）’９ｍ（ｌ中の１７β−ヒドロキシ−４−アンドロステン− ３−オン ５００ｍｇを滴加した。室温で撹拌し、３０分後に例１に記載したと 同様に後処理した。融点１４４−１４７℃の４−アンドロステン−１７β−オー ル ４００ｍｇが得られた。Example 2 5mi2 of trichloroacetic acid and 5m4 of acetonitrile while cooling with ice/water. , 370 mg of water-free sodium borohydride was added little by little. continuation , methylene chloride)'9m (17β-hydroxy-4-androstene- 500 mg of 3-one was added dropwise. Stir at room temperature and after 30 minutes as described in Example 1. It was post-treated in the same way. 4-androstene-17β-oh with melting point 144-147°C 400 mg of the product was obtained.
例 ３ 水不含の水素化ホウ素ナトリウム ５７０ｍｇを、氷／水で冷却しながら、内部 温度が＋１０°Ｃを上廻らないようにトリフルオロ酢酸５．５ｍ（１，酢酸５． ５ｍＱおよびアセトニトリルｌｏ＋ｉ（ｌに添加した。水素の発生が終了した後 に、この溶液を室温で、メチレンクロリド５ｍ（Ａ中の１７β−ヒドロキシ−４ −ニストレン−３−オン ２７４■に滴加し、３０分間撹拌し、飽和炭酸水素ナ トリウム溶液を注意深く添加した。引き続きメチレンクロリドで抽出し、水で洗 浄し、硫酸マグネシウムで乾燥した。粗製生成物を、メチレンクロリド／メタノ ール（９９＋１）を用いるシリカゲルのクロマトグラフィーによる精製により、 融点９６〜９９℃の４−ニストレン−１７β−オｉル ２１０１１９が得られた 例 ４ 水不含の水素化ホウ素ナトリウム ８００１１ｇを、氷／水で冷却しながら、内 部温度が＋１０℃を上廻らないように、トリクロロ酢酸７＋＋ＩＱ、ピバリン酸 ７ｍＱおよびアセトニトリルｌＱｍ（＋に添加した。水素化ホウ素ナトリウム溶 液を、室温で、メチレンクロリド８＋ｚ（１中の１７β−ヒドロキシ−４−ニス トレン−３−オン３８５■に滴加した。２０分後に、飽和炭酸水素ナトリウム溶 液を注意深く添加し、例３に記載したと同様に後処理した。メチレンクロリド／ メタノールを用いて、ンリカゲルで、粗製生成物をクロマトグラフィーにかけた 後に、融点９５〜９８℃の４−ニストレン−１７β−オール ２９０ＩＲｇが得 られｊ二。Example 3 While cooling 570 mg of water-free sodium borohydride with ice/water, 5.5 m of trifluoroacetic acid (1,5 m of acetic acid) so that the temperature does not exceed +10°C. 5 mQ and acetonitrile lo+i (l) were added after hydrogen evolution had finished. The solution was mixed at room temperature with 5 m of methylene chloride (17β-hydroxy-4 in A). -Nistrene-3-one was added dropwise to 274 cm, stirred for 30 minutes, and saturated hydrogen carbonate solution was added. Thorium solution was added carefully. Continue extraction with methylene chloride and wash with water. and dried over magnesium sulfate. The crude product was converted into methylene chloride/methano Purification by chromatography on silica gel using (99+1) 4-Nistrene-17β-oil 210119 with a melting point of 96-99°C was obtained. Example 4 80011g of water-free sodium borohydride was cooled with ice/water, Trichloroacetic acid 7++IQ, pivalic acid to prevent the temperature from exceeding +10°C. 7 mQ and acetonitrile 1Qm (+) added to the sodium borohydride solution. The solution was mixed with 17β-hydroxy-4-varnish in methylene chloride 8+z (1) at room temperature. It was added dropwise to 385 ml of tren-3-one. After 20 minutes, add saturated sodium bicarbonate solution. The liquid was carefully added and worked up as described in Example 3. Methylene chloride/ The crude product was chromatographed on glycerin gel using methanol. Later, 290IRg of 4-nystrene-17β-ol with a melting point of 95-98°C was obtained. There are two.
例 ５ 例３と同様に、１７β−ヒドロキシ−１８−メチル−４−ニストレン−３−オン ３００ｍｇを水素化ホウ素ナトリウムから製造した反応混合物と反応させた。Example 5 Similar to Example 3, 17β-hydroxy-18-methyl-4-nystren-3-one 300 mg were reacted with a reaction mixture prepared from sodium borohydride.
粗製生成物を、ヘキサン／酢酸エステルを用いシリカゲルのクロマトグラフィー により精製した後に、融点１１６〜１１７℃の１８−メチル−４−ニストレン− １７β−オール ２３０ｍｇが得られた。The crude product was chromatographed on silica gel using hexane/acetate. After purification by 18-methyl-4-nystrene- 230 mg of 17β-ol was obtained.
例 ６ 例３と同様に、１７ａ−エチニル−１７β−ヒドロキシ−４−ニストレン−３− オン ５００ｍｇを、水不含の水素化ホウ素ナトリウムから製造した反応混合物 と反応させた。この粗製生成物をアセトン中の活性炭で処理した後に、アセトン から再結晶させた。融点１６０〜１６２°Ｃの１７σ−エチニル−４−ニストレ ン−１７β−オール ３２０次ｇが得られた。Example 6 Similar to Example 3, 17a-ethynyl-17β-hydroxy-4-nystrene-3- Reaction mixture prepared from water-free sodium borohydride. I reacted. After treatment of this crude product with activated carbon in acetone, It was recrystallized from 17σ-ethynyl-4-nistre, melting point 160-162°C 320 grams of ion-17β-ol were obtained.
例 ７ 例３と同様に、１７α−エチニル−１７β−ヒドロキシ−１８−メチル−４−ニ ストレン−３−オン３５０１１ｇを、水不含の水素化ホウ素ナトリウムから製造 しｔ；反応混合物と反応させた。ヘキサン／酢酸エステルを用いたシリカゲルの クロマトグラフィーにかけた後に、融点５４℃の１７α−エチニル−１８−メチ ル−４−ニストレン−１７β−オール ２４０１１９ カ％うれた。Example 7 Similar to Example 3, 17α-ethynyl-17β-hydroxy-18-methyl-4-ni 35011 g of stren-3-one produced from water-free sodium borohydride and reacted with the reaction mixture. Silica gel preparation using hexane/acetate ester After chromatography, 17α-ethynyl-18-methylene, melting point 54°C, Lu-4-Nistrene-17β-ol yielded 240,119%.
例 ８ 例３と同様に、１７σ−エチニル−１８−メチル−１７β−ヒドロキシ−４，１ ５−エストラジェン−３−オン ２８０ｍｇを、水素化ホウ素ナトリウムから製 造した反応混合物と反応させた。この粗製生成物をヘキサン／酢酸エステルを用 いるシリカゲルのクロマトグラフィーにかけると、融点８２℃の１７ａ−エチニ ル−１８−メチル−４，１５−エストラジェン−１７β−オール １９０＋ＩＩ ｇが得られた。Example 8 Similar to Example 3, 17σ-ethynyl-18-methyl-17β-hydroxy-4,1 280 mg of 5-estradin-3-one was prepared from sodium borohydride. The mixture was reacted with the prepared reaction mixture. This crude product was purified using hexane/acetate. Chromatography on silica gel yields 17a-ethynyl with a melting point of 82°C. -18-methyl-4,15-estradine-17β-ol 190+II g was obtained.
例 ９ 例３と同様に、１７α−エチニル−１７β−ヒドロキシ−１８−メチル−１１− メチレン−４−ニストレン−３−オン ８３０１１１９を、水不含の水素化ホウ 素ナトリウムから製造した反応混合物と反応させた。粗製生成物を、ヘキサン／ 酢酸エステルを用いるシリカゲルのクロマトグラフィーにかけ、ヘキサンから再 結晶させた後に、融点１１０℃の１７σ−エチニル−１８−メチル−１１−メチ レン−４−ニストレン−１７β−オール ５６０１１ｇが得られた。Example 9 Similar to Example 3, 17α-ethynyl-17β-hydroxy-18-methyl-11- Methylene-4-nystren-3-one 8301119 was converted into water-free borohydride. It was reacted with a reaction mixture prepared from sodium chloride. The crude product was dissolved in hexane/ Chromatographed on silica gel using acetate and reconstituted from hexane. After crystallization, 17σ-ethynyl-18-methyl-11-methylene with a melting point of 110°C was obtained. 56011 g of ren-4-nistrene-17β-ol was obtained.
例 １０ 例３と同様に、１７−フェニル−４，１４，１６−アンドロスタトリエン−３− オン ６８０ｍｇを、水不含の水素化ホウ素ナトリウムから製造した反応混合物 と反応させｔ；。ヘキサン／酢酸エステルを用いてシリカゲルのクロマトグラフ ィーにかけた後に、融点９７℃のエアー７二二ルー４．１４．１６−アンドロス ドラトリエン ５５（１＋ｇが得られた。Example 10 Similar to Example 3, 17-phenyl-4,14,16-androstatriene-3- Reaction mixture prepared from water-free sodium borohydride. React with t;. Chromatograph on silica gel using hexane/acetate ester 722-4.14.16-Andros with a melting point of 97°C. Dolatriene 55 (1+g was obtained.
例 １１ 例３と同様に、１８−メチル−１７−フェニル−４，１４，１６−エスドラトリ エンー３−オン（融点１９１’０１１７−フェニル−４，１４，１６−エスドラ トリエンー３−オン（文献： Ｅ、 Ｗｉｎｔｅｒｆｅｌｄｔ ｅｔ ａｌ、。Example 11 Similar to Example 3, 18-methyl-17-phenyl-4,14,16-esdratri en-3-one (melting point 191'0117-phenyl-4,14,16-esdra Trien-3-one (Reference: E, Winterfeldt et al.
Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒ、 ２７ ＋ ５８３３ （１９８６） ））９３０ｍｇを、水不含の水素化ホウ素ナトリウムから製造した反応混合物 と反応させた。粗製生成物を、ヘキサン／酢酸エステルを用いるシリカゲルのク ロマトグラフィーにかけた後に、融点９３．５℃の１８−メチル−１７−フェニ ル−４，１４，１６−エストラトリエン ７３０聰ｔが得られた。Tetrahedron Letter, 27 + 5833 (1986) )) 930 mg of reaction mixture prepared from water-free sodium borohydride I reacted. The crude product was filtered onto silica gel using hexane/acetate. After chromatography, 18-methyl-17-phenylene with a melting point of 93.5°C was obtained. 730 tons of Ru-4,14,16-estratriene were obtained.
例 １２ 例３と同様に、１７１ｔ−クロロエチニル−１７β−ヒドロキシ−１８−メチル −１１−メチレン−４−ニストレン−３−オン ３６０ｍ＋９を、水不含の水素 化ホウ素ナトリウムから製造した反応混合物と反応させた。粗製生成物を、ヘキ サン／酢酸エステルを用いるシリカゲルのクロマトグラフィーにかけた後に、融 点１６５℃の１７．ｒ−クロロエチニル−１８−メチル−１ｌ−メチレン−４− ニストレン−１７β−オール２３０１１９が得られた。Example 12 Similar to Example 3, 171t-chloroethynyl-17β-hydroxy-18-methyl -11-methylene-4-nystren-3-one 360m+9, water-free hydrogen It was reacted with a reaction mixture prepared from sodium boronate. The crude product was After chromatography on silica gel using San/Acetate, 17 at point 165°C. r-chloroethynyl-18-methyl-1l-methylene-4- Nistren-17β-ol 230119 was obtained.
例 １３ 例３と同様に、１８−メチル−１１−メチレン−４−ニストレン−３，１７−ジ オン ６８０１１９を、水不含の水素化ホウ素ナトリウムから製造した反応混合 物と反応させた。こうして得られた粗製生成物（６００ｍ＋９ ）をアセトンｌ ｏ＋Ｑ中で８Ｎミ酸化クロム／硫酸−溶液（ジジーンズ試薬）０．８＋Ｑと反応 させた。この反応混合物を氷／水中に注いだ。沈殿した生成物を吸引濾過し、水 で洗浄し、乾燥した。ヘキサン／酢酸エステルを用いたシリカゲルのクロマトグ ラフィーにかけ、ジエチルエーテルから再結晶させた後に、融点９８℃の１８− メチル−１１−メチレン−４−ニストレン−１７−オン ３４０１１９が得られ た。Example 13 Similar to Example 3, 18-methyl-11-methylene-4-nistrene-3,17-di 680119 from water-free sodium borohydride reacted with things. The crude product thus obtained (600m+9) was mixed with 1 acetone. React with 8N chromium dioxide/sulfuric acid solution (Gijens reagent) in 0.8+Q I let it happen. The reaction mixture was poured into ice/water. The precipitated product is filtered with suction and washed with water. Washed and dried. Silica gel chromatograph using hexane/acetate ester After drying and recrystallizing from diethyl ether, 18- Methyl-11-methylene-4-nistrene-17-one 340119 was obtained. Ta.
国際調査報告 国際調査報告 ＴＮ＋″°”゛“°゛１°゛゛′”°゛°”°”−１“パ′。゛１哨゛°′″轡 °パ０°°“”１”−晰°−“′δ７ン♂ζン醪“０”−Ｔｍｍｅｍｂｅｒ＠ｒ ｅＭｌｃａｅ＋ｕｅｅｇ＋Ｒ１ｈ＠（ｖｆｆｉ紳＃＃すｆｅｅｌＯｌｌｌｔｅ［ ＤＰｌ＋１−＋＋ｓτ−εｕｒａ＃ｓｅ Ｐａ＋Ｎ＋ ５ｌｉｃｅ ＩＩ ｌ＃ ａｓ 豐ｍＶ １１８６１＠ １６１ 自６會ｕ＋’＋＋ｃｗ・ａｎ Ｍｉｅ ■@ａｎ １Ｒｅｌｌｌｌｙ ｇ：ｖｍ １ｗ ＋ｈｓ ＃１ｊＩｌ ｅｌ １ ｅＬｏｒ＋ｗａｌｌｅａ。international search report international search report TN+″°”゛“°゛1°゛゛′”°゛°”°”−1 “Pa′. °Pa0°°""1"-lucid°-"'δ7n♂ζnmomi"0"-Tmmember@r eMlcae+ueeg+R1h@(vffi gentleman ##feelOllte[ DPl+1-++sτ-εura#se Pa+N+ 5lice II l# as 豐mV 11861 @ 161 self 6 meeting u+’++cw・an Mie ■@an 1Relly g:vm 1w +hs #1jIl el 1 eLor+wallea.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3909770A DE3909770A1 (en) | 1989-03-21 | 1989-03-21 | METHOD FOR PRODUCING 3-DESOXY-4-EN STEROIDS |
| DE3909770.6 | 1989-03-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03505740A true JPH03505740A (en) | 1991-12-12 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2504118A Pending JPH03505740A (en) | 1989-03-21 | 1990-03-08 | Method for producing 3-desoxy-4-ene steroid |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5140106A (en) |
| EP (1) | EP0440752B1 (en) |
| JP (1) | JPH03505740A (en) |
| AT (1) | ATE119542T1 (en) |
| DD (1) | DD292916A5 (en) |
| DE (2) | DE3909770A1 (en) |
| DK (1) | DK0440752T3 (en) |
| ES (1) | ES2069735T3 (en) |
| WO (1) | WO1990011290A1 (en) |
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| DE4330727C2 (en) * | 1993-09-10 | 1998-02-19 | Jenapharm Gmbh | Steroid intermediates and processes for their manufacture |
| US5952319A (en) * | 1997-11-26 | 1999-09-14 | Research Triangle Institute | Androgenic steroid compounds and a method of making and using the same |
| US7402577B2 (en) * | 2001-10-03 | 2008-07-22 | Merck & Co., Inc. | Androstane 17-beta-carboxamides as androgen receptor modulators |
| ITMI20021755A1 (en) | 2002-08-02 | 2002-11-01 | Poli Ind Chimica Spa | PROCESS AND NEW INTERMEDIATES FOR THE PREPARATION OF STEROIDS FOR PROGESTINIC ACTIVITIES. |
| CN103215328B (en) | 2004-01-21 | 2016-08-03 | 诺和诺德医疗保健公司 | The joint of transglutaminase mediated peptide |
| CN105237606B (en) * | 2014-07-11 | 2018-08-24 | 上海创诺制药有限公司 | It is a kind of to be used to synthesize intermediate of Desogestrel and its preparation method and application |
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| US3099656A (en) * | 1962-02-26 | 1963-07-30 | Syntex Corp | delta3,5-pregnadiene derivatives |
| US3471531A (en) * | 1966-04-07 | 1969-10-07 | Herchel Smith | Synthesis of gona-3,5-dienes |
| NL7017428A (en) * | 1970-11-28 | 1972-05-30 | ||
| DE3005374A1 (en) * | 1980-02-11 | 1981-08-20 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | 3-DESOXY-DELTA HIGH 15-STEROIDS, METHOD FOR THE PRODUCTION THEREOF AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
-
1989
- 1989-03-21 DE DE3909770A patent/DE3909770A1/en not_active Withdrawn
-
1990
- 1990-03-08 DK DK90904244.2T patent/DK0440752T3/en active
- 1990-03-08 EP EP90904244A patent/EP0440752B1/en not_active Expired - Lifetime
- 1990-03-08 DE DE59008652T patent/DE59008652D1/en not_active Expired - Lifetime
- 1990-03-08 JP JP2504118A patent/JPH03505740A/en active Pending
- 1990-03-08 ES ES90904244T patent/ES2069735T3/en not_active Expired - Lifetime
- 1990-03-08 WO PCT/DE1990/000183 patent/WO1990011290A1/en active IP Right Grant
- 1990-03-08 AT AT90904244T patent/ATE119542T1/en not_active IP Right Cessation
- 1990-03-08 US US07/646,750 patent/US5140106A/en not_active Expired - Fee Related
- 1990-03-19 DD DD90338858A patent/DD292916A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0440752A1 (en) | 1991-08-14 |
| WO1990011290A1 (en) | 1990-10-04 |
| US5140106A (en) | 1992-08-18 |
| DE59008652D1 (en) | 1995-04-13 |
| ES2069735T3 (en) | 1995-05-16 |
| DD292916A5 (en) | 1991-08-14 |
| ATE119542T1 (en) | 1995-03-15 |
| DK0440752T3 (en) | 1995-07-24 |
| EP0440752B1 (en) | 1995-03-08 |
| DE3909770A1 (en) | 1990-09-27 |
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